Prevacid (Lansoprazole) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

PHARMACOKINETICS AND METABOLISM

PREVACID Delayed-Release Capsules, PREVACID SoluTab Delayed-Release Orally Disintegrating Tablets and PREVACID for Delayed-Release Oral Suspension contain an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. Absorption is rapid, with mean peak plasma levels of lansoprazole occurring after approximately 1.7 hours. Peak plasma concentrations of lansoprazole (C_max) and the area under the plasma concentration curve (AUC) of lansoprazole are approximately proportional in doses from 15 mg to 60 mg after single-oral administration. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.

ABSORPTION

The absorption of lansoprazole is rapid, with mean C_max occurring approximately 1.7 hours after oral dosing, and relatively complete with absolute bioavailability over 80%. In healthy subjects, the mean (±SD) plasma half-life was 1.5 (±1.0) hours. Both C_max and AUC are diminished by about 50% to 70% if the drug is given 30 minutes after food as opposed to the fasting condition. There is no significant food effect if the drug is given before meals.

DISTRIBUTION

Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5.0 µg/mL.

METABOLISM

Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active species which inhibit acid secretion by (H⁺,K⁺)-ATPase within the parietal cell canaliculus, but are not present in the systemic circulation. The plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion. Thus, the plasma elimination half-life is less than two hours, while the acid inhibitory effect lasts more than 24 hours.

ELIMINATION

Following single-dose oral administration of lansoprazole, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of¹⁴ C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the metabolites of lansoprazole.

SPECIAL POPULATIONS

Geriatric

The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly. No dosage adjustment is necessary in the elderly.

Pediatric

The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged 1 to 11 years and 12 to 17 years in two separate clinical studies. In children aged 1 to 11 years, lansoprazole was dosed 15 mg q.d. for subjects weighing 30 kg. Mean C_max and AUC values observed on Day 5 of dosing were similar between the two dose groups and were not affected by weight or age within each weight-adjusted dose group used in the study. In adolescent subjects aged 12 to 17 years, subjects were randomized to receive lansoprazole at 15 mg or 30 mg q.d. Mean C_max and AUC values of lansoprazole were not affected by body weight or age; and nearly dose-proportional increases in mean C_max and AUC values were observed between the two dose groups in the study. Overall, lansoprazole pharmacokinetics in pediatric patients aged 1 to 17 years were similar to those observed in healthy adult subjects.

Gender

In a study comparing 12 male and 6 female human subjects, no gender differences were found in pharmacokinetics and intragastric pH results. (Also see Use in Women.)

Renal Insufficiency

In patients with severe renal insufficiency, plasma protein binding decreased by 1.0%-1.5% after administration of 60 mg of lansoprazole. Patients with renal insufficiency had a shortened elimination half-life and decreased total AUC (free and bound). AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment, and C_max and T_max were not different from subjects with healthy kidneys. No dosage adjustment is necessary in patients with renal insufficiency.

Hepatic Insufficiency

In patients with various degrees of chronic hepatic disease, the mean plasma half-life of the drug was prolonged from 1.5 hours to 3.2-7.2 hours. An increase in mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Dose reduction in patients with severe hepatic disease should be considered.

Race

The pooled mean pharmacokinetic parameters of lansoprazole from twelve U.S. Phase 1 studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of lansoprazole in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The C_max values were comparable.

PHARMACODYNAMICS

MECHANISM OF ACTION

Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or histamine H₂-receptor antagonist properties, but that suppress gastric acid secretion by specific inhibition of the (H⁺,K⁺)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus.

ANTISECRETORY ACTIVITY

After oral administration, lansoprazole was shown to significantly decrease the basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH was >3 and >4. Lansoprazole also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and acid output induced by insulin.

In a crossover study that included lansoprazole 15 and 30 mg for five days, the following effects on intragastric pH were noted:

After the initial dose in this study, increased gastric pH was seen within 1-2 hours with lansoprazole 30 mg and 2-3 hours with lansoprazole 15 mg. After multiple daily dosing, increased gastric pH was seen within the first hour postdosing with lansoprazole 30 mg and within 1-2 hours postdosing with lansoprazole 15 mg.

Acid suppression may enhance the effect of antimicrobials in eradicating Helicobacter pylori (H. pylori). The percentage of time gastric pH was elevated above 5 and 6 was evaluated in a crossover study of PREVACID given q.d., b.i.d. and t.i.d.

The inhibition of gastric acid secretion as measured by intragastric pH returns gradually to normal over two to four days after multiple doses. There is no indication of rebound gastric acidity.

ENTEROCHROMAFFIN-LIKE (ECL) CELL EFFECTS

During lifetime exposure of rats with up to 150 mg/kg/day of lansoprazole dosed seven days per week, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats. (See PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility.)

Gastric biopsy specimens from the body of the stomach from approximately 150 patients treated continuously with lansoprazole for at least one year did not show evidence of ECL cell effects similar to those seen in rat studies. Longer term data are needed to rule out the possibility of an increased risk of the development of gastric tumors in patients receiving long-term therapy with lansoprazole.

OTHER GASTRIC EFFECTS IN HUMANS

Lansoprazole did not significantly affect mucosal blood flow in the fundus of the stomach. Due to the normal physiologic effect caused by the inhibition of gastric acid secretion, a decrease of about 17% in blood flow in the antrum, pylorus, and duodenal bulb was seen. Lansoprazole significantly slowed the gastric emptying of digestible solids. Lansoprazole increased serum pepsinogen levels and decreased pepsin activity under basal conditions and in response to meal stimulation or insulin injection. As with other agents that elevate intragastric pH, increases in gastric pH were associated with increases in nitrate-reducing bacteria and elevation of nitrite concentration in gastric juice in patients with gastric ulcer. No significant increase in nitrosamine concentrations was observed.

SERUM GASTRIN EFFECTS

In over 2100 patients, median fasting serum gastrin levels increased 50% to 100% from baseline but remained within normal range after treatment with lansoprazole given orally in doses of 15 mg to 60 mg. These elevations reached a plateau within two months of therapy and returned to pretreatment levels within four weeks after discontinuation of therapy.

ENDOCRINE EFFECTS

Human studies for up to one year have not detected any clinically significant effects on the endocrine system. Hormones studied include testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), prolactin, cortisol, estradiol, insulin, aldosterone, parathormone, glucagon, thyroid stimulating hormone (TSH), triiodothyronine (T₃), thyroxine (T₄), and somatotropic hormone (STH). Lansoprazole in oral doses of 15 to 60 mg for up to one year had no clinically significant effect on sexual function. In addition, lansoprazole in oral doses of 15 to 60 mg for two to eight weeks had no clinically significant effect on thyroid function.

In 24-month carcinogenicity studies in Sprague-Dawley rats with daily dosages up to 150 mg/kg, proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared to control rates.

OTHER EFFECTS

No systemic effects of lansoprazole on the central nervous system, lymphoid, hematopoietic, renal, hepatic, cardiovascular or respiratory systems have been found in humans. No visual toxicity was observed among 56 patients who had extensive baseline eye evaluations, were treated with up to 180 mg/day of lansoprazole and were observed for up to 58 months. Other rat-specific findings after lifetime exposure included focal pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus, and spontaneous retinal atrophy.

MICROBIOLOGY

Lansoprazole, clarithromycin and/or amoxicillin have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

HELICOBACTER
HELICOBACTER PYLORI

Pretreatment Resistance

Clarithromycin pretreatment resistance (>/=2.0 µg/mL) was 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the dual and triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).

Amoxicillin pretreatment susceptible isolates (0.25 µg/mL. One patient on the 14-day triple therapy regimen had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of >256 µg/mL by E-test and the patient was eradicated of H. pylori.

Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done when possible. Patients with clarithromycin resistant H. pylori should not be treated with lansoprazole/amoxicillin/clarithromycin triple therapy or with regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (H. pylori. Of those with pretreatment amoxicillin MICs of >0.25 µg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg t.i.d./amoxicillin 1 gm t.i.d. dual therapy and a total of 12.8% (22/172) of the patients failed the 10- and 14-day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs. ¹ One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 × 10⁷- 1 × 10⁸ CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial-containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (>/= 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for campylobacters. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values: